Myelin pathology: Involvement of molecular chaperones and the promise of chaperonotherapy

The process of axon myelination involves various proteins including molecular chaperones. Myelin alteration is a common feature in neurological diseases due to structural and functional abnormalities of one or more myelin proteins. Genetic proteinopathies may occur either in the presence of a normal chaperoning system, which is unable to assist the defective myelin protein in its folding and migration, or due to mutations in chaperone genes, leading to functional defects in assisting myelin maturation/migration. The latter are a subgroup of genetic chaperonopathies causing demyelination. In this brief review, we describe some paradigmatic examples pertaining to the chaperonins Hsp60 (HSPD1, or HSP60, or Cpn60) and CCT (chaperonin-containing TCP-1). Our aim is to make scientists and physicians aware of the possibility and advantages of classifying patients depending on the presence or absence of a chaperonopathy. In turn, this subclassification will allow the development of novel therapeutic strategies (chaperonotherapy) by using molecular chaperones as agents or targets for treatment

Low-cost sensors based multi-sensor data fusion techniques for RPAS navigation and guidance

In order for Remotely Piloted Aircraft Systems (RPAS) to coexist seamlessly with manned aircraft in non-segregated airspace, enhanced navigational capabilities are essential to meet the Required Navigational Performance (RNP) levels in all flight phases. A Multi-Sensor Data Fusion (MSDF) framework is adopted to improve the navigation capabilities of an integrated Navigation and Guidance System (NGS) designed for small-sized RPAS. The MSDF architecture includes low-cost and low weight/volume navigation sensors suitable for various classes of RPAS. The selected sensors include Global Navigation Satellite Systems (GNSS), Micro-Electro-Mechanical System (MEMS) based Inertial Measurement Unit (IMU) and Vision Based Sensors (VBS). A loosely integrated navigation architecture is presented where an Unscented Kalman Filter (UKF) is used to combine the navigation sensor measurements. The presented UKF based VBS-INS-GNSS-ADM (U-VIGA) architecture is an evolution of previous research performed on Extended Kalman Filter (EKF) based VBS-INS-GNSS (E-VIGA) systems. An Aircraft Dynamics Model (ADM) is adopted as a virtual sensor and acts as a knowledge-based module providing additional position and attitude information, which is pre-processed by an additional/local UKF. The E-VIGA and U-VIGA performances are evaluated in a small RPAS integration scheme (i.e., AEROSONDE RPAS platform) by exploring a representative cross-section of this RPAS operational flight envelope. The position and attitude accuracy comparison shows that the E-VIGA and U-VIGA systems fulfill the relevant RNP criteria, including precision approach in CAT-II. A novel Human Machine Interface (HMI) architecture is also presented, whose design takes into consideration the coordination tasks of multiple human operators. In addition, the interface scheme incorporates the human operator as an integral part of the control loop providing a higher level of situational awareness

Reply: Is CD1a involved in antitumour immune responses during carcinogenesis?

© 2004 Cancer Research UKPresents a response by the authors to a letter to the editor about their article "Is CD1a involved in antitumour immune responses during carcinogenesis?," published in the February 23, 2004 issue of the "British Journal of Cancer"B.J. Coventry and S. Heinze

The Major Heat Shock Proteins, Hsp70 and Hsp90, in 2-Methoxyestradiol-Mediated Osteosarcoma Cell Death Model

2-Methoxyestradiol is one of the natural 17β-estradiol derivatives and a potential novel anticancer agent currently being under evaluation in advanced phases of clinical trials. However, the mechanism of anticancer action of 2-methoxyestradiol has not been yet fully established. In our previous studies we have demonstrated that 2-methoxyestradiol selectively induces the expression and nuclear translocation of neuronal nitric oxide synthase in osteosarcoma 143B cells. Heat shock proteins (Hsps) are factors involved in the regulation of expression and activity of nitric oxide synthases. Herein, we chose osteosarcoma cell lines differed in metastatic potential, metastatic 143B and highly metastatic MG63.2 cells, in order to further investigate the anticancer mechanism of 2-methoxyestradiol. The current study aimed to determine the role of major heat shock proteins, Hsp90 and Hsp70 in 2-methoxyestradiol-induced osteosarcoma cell death. We focused on the implication of Hsp90 and Hsp70 in control under expression of neuronal nitric oxide synthase, localization of the enzyme, and further generation of nitro-oxidative stress. To give the insight into the role of Hsp90 in regulation of anticancer efficacy of 2-methoxyestradiol, we used geldanamycin as a potent Hsp90 inhibitor. Herein, we evidenced that inhibition of Hsp90 controls the protein expression of 2-methoxyestradiol-induced neuronal nitric oxide synthase and inhibits enzyme nuclear translocation. We propose that decreased level of neuronal nitric oxide synthase protein after a combined treatment with 2-methoxyestradiol and geldanamycin is directly associated with the accompanying upregulation of Hsp70 and downregulation of Hsp90. This interaction resulted in abrogation of anticancer efficacy of 2-methoxyestradiol by geldanamycin

QVAST: a new Quantum GIS plugin for estimating volcanic susceptibility

One of the most important tasks of modern volcanology is the construction of hazard maps simulating different eruptive scenarios that can be used in risk-based decision making in land-use planning and emergency management. The first step in the quantitative assessment of volcanic hazards is the development of susceptibility maps (i.e., the spatial probability of a future vent opening given the past eruptive activity of a volcano). This challenging issue is generally tackled using probabilistic methods that use the calculation of a kernel function at each data location to estimate probability density functions (PDFs). The smoothness and the modeling ability of the kernel function are controlled by the smoothing parameter, also known as the bandwidth. Here we present a new tool, QVAST, part of the open-source geographic information system Quantum GIS, which is designed to create user-friendly quantitative assessments of volcanic susceptibility. QVAST allows the selection of an appropriate method for evaluating the bandwidth for the kernel function on the basis of the input parameters and the shapefile geometry, and can also evaluate the PDF with the Gaussian kernel. When different input data sets are available for the area, the total susceptibility map is obtained by assigning different weights to each of the PDFs, which are then combined via a weighted summation and modeled in a non-homogeneous Poisson process. The potential of QVAST, developed in a free and user-friendly environment, is here shown through its application in the volcanic fields of Lanzarote (Canary Islands) and La Garrotxa (NE Spain)

SARS-CoV-2 in patients with cancer: possible role of mimicry of human molecules by viral proteins and the resulting anti-cancer immunity

A few reports suggest that molecular mimicry can have a role in determining the more severe and deadly forms of COVID-19, inducing endothelial damage, disseminated intravascular coagulation, and multiorgan failure. Heat shock proteins/molecular chaperones can be involved in these molecular mimicry phenomena. However, tumor cells can display on their surface heat shock proteins/molecular chaperones that are mimicked by SARS-CoV-2 molecules (including the Spike protein), similarly to what happens in other bacterial or viral infections. Since molecular mimicry between SARS-CoV-2 and tumoral proteins can elicit an immune reaction in which antibodies or cytotoxic cells produced against the virus cross-react with the tumor cells, we want to prompt clinical studies to evaluate the impact of SARS-CoV-2 infection on prognosis and follow up of various forms of tumors. These topics, including a brief historical overview, are discussed in this paper

Robot-aided assessment of wrist proprioception

Introduction: Impaired proprioception severely affects the control of gross and fine motor function. However, clinical assessment of proprioceptive deficits and its impact on motor function has been difficult to elucidate. Recent advances in haptic robotic interfaces designed for sensorimotor rehabilitation enabled the use of such devices for the assessment of proprioceptive function. Purpose: This study evaluated the feasibility of a wrist robot system to determine proprioceptive discrimination thresholds for two different DoFs of the wrist. Specifically, we sought to accomplish three aims: first, to establish data validity; second, to show that the system is sensitive to detect small differences in acuity; third, to establish test–retest reliability over repeated testing. Methodology: Eleven healthy adult subjects experienced two passive wrist movements and had to verbally indicate which movement had the larger amplitude. Based on a subject’s response data, a psychometric function was fitted and the wrist acuity threshold was established at the 75% correct response level. A subset of five subjects repeated the experimentation three times (T1, T2, and T3) to determine the test–retest reliability. Results: Mean threshold for wrist flexion was 2.15° ± 0.43° and 1.52° ± 0.36° for abduction. Encoder resolutions were 0.0075° (flexion–extension) and 0.0032° (abduction–adduction). Motor resolutions were 0.2°(flexion–extension) and 0.3° (abduction–adduction). Reliability coefficients were rT2-T1 = 0.986 and rT3-T2 = 0.971. Conclusion: We currently lack established norm data on the proprioceptive acuity of the wrist to establish direct validity. However, the magnitude of our reported thresholds is physiological, plausible, and well in line with available threshold data obtained at the elbow joint. Moreover, system has high resolution and is sensitive enough to detect small differences in acuity. Finally, the system produces reliable data over repeated testing